tbuckley/cabot-search huggingface dataset:
Abstract PR005: Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3’ untranslated region mutations
Authors: Samantha L. Schuster, Sonali Arora, Cynthia L. Wladyka, Lukas Corey, Bethany L. Stackhouse, Lori Kollath, Eva Corey, Lawrence D. True, Dave Young, Patrick J. Paddison, Andrew C. Hsieh
Journal: Cancer Research (2023)

Abstract It is clear from the high mortality rate in advanced cancers that we need a more complete understanding of the many sources of oncogenic dysregulation in tumors. The importance of the non-coding genome in disease has recently begun to be revealed through expanded use of whole genome sequencing. In particular, 3’ untranslated region (3’UTR) somatic mutations represent an important but largely unexplored avenue of alternative oncogenic gene dysregulation. Individual instances of 3’UTR-mediated oncogenicity are known, including oncogenic RNA binding proteins and microRNAs. However, a comprehensive, high-throughput study of patient-based 3’UTR mutations and their effect on post-transcriptional gene regulation in cancer has yet to be undertaken. To determine the significance of 3’UTR mutations in advanced disease, we identify 3’UTR somatic variants across 185 metastatic castration-resistant prostate tumors, discovering 14,497 single-nucleotide mutations, which are enriched in oncogenic pathways and 3’UTR regulatory elements. We develop two complementary massively parallel reporter assays (MPRAs) to measure how thousands of these patient-based mutations affect two distinct levels of post-transcriptional gene regulation: mRNA translation and stability. These MPRAs identify hundreds of functional variants that allow us to define three determinants of mutation significance: sequence conservation, known regulatory elements, and RNA structure. Furthermore, we demonstrate the clinical relevance of these mutations, observing that CRISPR-Cas9 base editing of distinct patient 3’UTR mutations into endogenous cellular loci increases oncogenic mRNA translation and cellular stress resistance. Finally, we go back to patients, illustrating that those harboring oncogenic 3’UTR mutations discovered by our methods display particularly poor prognosis. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation, and cancer progression, uncovering principles of regulatory functionality and potential therapeutic targets in previously unexplored regulatory regions. Citation Format: Samantha L. Schuster, Sonali Arora, Cynthia L. Wladyka, Lukas Corey, Bethany L. Stackhouse, Lori Kollath, Eva Corey, Lawrence D. True, Dave Young, Patrick J. Paddison, Andrew C. Hsieh. Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3’ untranslated region mutations [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR005.
Abstract PR007: ERG-driven luminal prostate cancers emerge from Ck5+/Nkx3.1+ basal cells
Authors: Weiran Feng, Erik Ladewig, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Ignas Masilionis, Katia Manova-Todorova, Ronan Chaligné, Elisa de Stanchina, Brett S. Carver, Yu Chen, Dong Gao, Christina S. Leslie, Charles L. Sawyers
Journal: Cancer Research (2023)

Abstract TMPRSS2-ERG translocations are initiating lesions in nearly 50% of human prostate adenocarcinomas, often in conjunction with PTEN loss. In mice, prostate-specific expression of ERG using a Probasin-Cre driver (Pb-Cre4) is sufficient to induce invasive Ck8+ luminal adenocarcinoma with high penetrance in the context of Pten loss. Because TMPRSS2 expression in the human prostate is androgen-regulated and thereby largely restricted to luminal epithelial cells, it has been assumed that luminal cells are the likely cell of origin for TMPRSS2-ERG positive prostate cancers. To gain further support for this hypothesis, we examined the early stages of luminal adenocarcinoma initiation in the Pb-Cre ERG/Pten model at a single cell level. To our surprise, we found a highly proliferative population of ERG+ Ck5+ (a putative basal marker) cells that are enriched at the invasive front in a background of more canonical ERG+/Ck8+/Ck5- luminal tumor cells. We next performed lineage tracing experiments using Ck5-, Ck8- as well as Nkx3.1-Cre drivers, introduced via viral injection or tamoxifen induction, which collectively support the hypothesis that ERG-driven tumors originate in a subset of basal cells defined by Ck5+/Nkx3.1+. This conclusion is further supported by orthotopic transplantation of freshly isolated primary mouse prostate basal (Cd49f high) or luminal (Cd24 high) cells showing that ERG+/Ck8+ tumors arise preferentially from basal cells following ex vivo ERG/Pten activation. Time course experiments in organoids and in vivo show that ERG promotes Ck8+ luminal differentiation from highly proliferative Ck5+ cells, progressing through a Ck5+/Ck8+ intermediate cell state. Collectively, these data implicate a tumor initiating cell population defined by a mix of basal (Ck5) and luminal (Nkx3.1) markers that, under the influence of ERG expression, can expand and invade while retaining full luminal differentiation potential. Our results also suggest that widely held assumptions regarding luminal-specific expression of canonical markers such as Nkx3.1 and Probasin may need revision. Citation Format: Weiran Feng, Erik Ladewig, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Ignas Masilionis, Katia Manova-Todorova, Ronan Chaligné, Elisa de Stanchina, Brett S. Carver, Yu Chen, Dong Gao, Christina S. Leslie, Charles L. Sawyers. ERG-driven luminal prostate cancers emerge from Ck5+/Nkx3.1+ basal cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR007.
Abstract B067: CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells
Authors: Rajendra Kumar, Janet Mendonca, Yuhan Yang, Abhishek Shetty, Lillian Wilson, Kavya Boyapati, Deven Topiwala, Keerti Soundappan, Eleni Panagopoulos, Michael Carducci, Sushant Kachhap
Journal: Cancer Research (2023)

Abstract Background: Advanced metastatic prostate cancer is the second leading cause of death in men in the United States. Androgen deprivation therapy has been used as a front-line therapy; however, despite initial success, it fails subsequently and results in the development of castration-resistant prostate cancer. Due to these unmet therapeutic needs, there is an urgency to identify novel targets to develop next-generation therapeutics. Chromosome region maintenance 1 (CRM1) is one of the seven members of mammalian export proteins that function to export the proteins using nuclear export signal (NES). Several tumors, including prostate cancer, overexpress CRM1 to efflux tumor suppressor proteins to the cytoplasm and exhibit dysregulated nuclear export. CRM1-mediated export can lead to functional inactivation of p53, cyclinD1, p16, p21, and p27. Essential DNA repair proteins such as Rad51 and BRCA1 exhibit leucine-containing hydrophobic residues rich in NES and are known to be shuttled by CRM1. Based on this, we hypothesize that CRM1 inhibition may affect the expression, kinetics, localization, and stability of DNA repair network proteins. Methods: Androgen receptor-positive and negative prostate cancer cells were treated with Selinexor. The dose of the drug and duration was dependent on the endpoint measurement. Cell death was monitored using MTT assay and western blot measurement of cleaved PARP. Total RNA and cell lysate were collected to measure the relative levels of BRCA-1, RAD51, p53, and other members of the DNA repair pathway (HR and NHEJ). DNA damage was estimated using the number of micronuclei and immunofluorescence staining for γ-H2AX and COMET assay. Results: Selinexor treatment in prostate cancer cells affects the functioning of the DNA repair network and can be combined with inhibitors of DNA repair proteins. Citation Format: Rajendra Kumar, Janet Mendonca, Yuhan Yang, Abhishek Shetty, Lillian Wilson, Kavya Boyapati, Deven Topiwala, Keerti Soundappan, Eleni Panagopoulos, Michael Carducci, Sushant Kachhap. CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B067.
Abstract A085: A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis
Authors: Fu Luo, Lara F. Tshering, Karis Tutuska, Mariola Szenk, Diana Rubel, James G. Rail, Savanah Russ, Jingxuan Liu, Alice Nemajerova, Gábor Balázsi, Flaminia Talos
Journal: Cancer Research (2023)

Abstract Cellular heterogeneity poses tremendous challenges for developing cell-targeted therapies and biomarkers of clinically significant prostate cancer. The origins of this heterogeneity within the cellular complexities of normal adult and aging tissue remain unknown leaving important cellular states and transcriptional programs that allow the expansion of malignant clones in early cancer unidentified. These unresolved questions hamper the development of novel therapies designed to block the deregulated proliferation of prostate epithelial cells. To define cell states that contribute to early cancer development, we performed in vivo lineage tracing with multicolor reporters, whole organ mapping and single cell transcriptomics of normal and malignant prostate from genetically-engineered mouse models. We show here that the long-term luminal homeostasis is maintained by multiple clones with various fitness levels. Long-term clonal expansions are enabled by a luminal transcriptional state harboring basal markers (Luminal Intermediate, LumI) and controlled by Wnt/p63 signaling. Moreover, LumI cells greatly expand during early stages of tumorigenesis in several mouse models of prostate cancer. Specific genetic ablation of p63 from luminal cells in vivo decreases clonal activity in homeostasis and reduces the formation of aggressive clones in prostate tumor models. Finally, the LumI cells and Wnt signaling appear to significantly increase in human aging prostate and prostate cancer samples, highlighting the importance of this hybrid cell state for human pathologies with potential translational impact. Our models reveal a continuity of this cell state from normal homeostasis to aging and early cancer with specific alterations at each stage. Understanding how the luminal intermediate cell state is regulated in homeostasis and deregulated in hyperproliferative contexts is crucial for the development of prognostic markers and new therapeutic interventions for prostate diseases. Citation Format: Fu Luo, Lara F. Tshering, Karis Tutuska, Mariola Szenk, Diana Rubel, James G. Rail, Savanah Russ, Jingxuan Liu, Alice Nemajerova, Gábor Balázsi, Flaminia Talos. A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A085.
Identification of host regulators of Mycobacterium tuberculosis phenotypes uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence
Authors: Haroon Kalam, Chih-Hung Chou, Motohiko Kadoki, Daniel B. Graham, Jacques Deguine, Deborah T. Hung, Ramnik J. Xavier
Journal: Cell Host & Microbe (2023)
Human skin-resident CD8+ T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a
Authors: Beatrice Zitti, Elena Hoffer, Wenning Zheng, Ram Vinay Pandey, Heinrich Schlums, Giovanna Perinetti Casoni, Irene Fusi, Lien Nguyen, Jaanika Kärner, Efthymia Kokkinou, Anna Carrasco, Jessica Gahm, Marcus Ehrström, Staffan Happaniemi, Åsa V. Keita, Charlotte R.H. Hedin, Jenny Mjösberg, Liv Eidsmo, Yenan T. Bryceson
Journal: Immunity (2023)
Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results
Authors: Priscilla K. Brastianos, Albert E. Kim, Anita Giobbie-Hurder, Eudocia Q. Lee, Nancy U. Lin, Beth Overmoyer, Patrick Y. Wen, Lakshmi Nayak, Justine V. Cohen, Jorg Dietrich, April Eichler, Rebecca S. Heist, Ian Krop, Donald Lawrence, Jennifer Ligibel, Sara Tolaney, Erica Mayer, Eric Winer, Brittany Bent, Magali A. de Sauvage, Nazanin Ijad, Juliana M. Larson, Braxton Marion, Sally Nason, Naina Murthy, Sherry Ratcliff, Elizabeth J. Summers, Maura Mahar, Helen A. Shih, Kevin Oh, Daniel P. Cahill, Elizabeth R. Gerstner, Ryan J. Sullivan
Journal: Nature Medicine (2023)
Cis- and trans-eQTM analysis reveals novel epigenetic and transcriptomic immune markers of atopic asthma in airway epithelium
Authors: Soyeon Kim, Zhongli Xu, Erick Forno, Yidi Qin, Hyun Jung Park, Molin Yue, Qi Yan, Michelle L. Manni, Edna Acosta-Pérez, Glorisa Canino, Wei Chen, Juan C. Celedón
Journal: Journal of Allergy and Clinical Immunology (2023)
Screening for Lung Cancer: An Expert Review
Authors: Ella A. Kazerooni, Jacob Sands, Douglas E. Wood
Journal: Journal of the National Comprehensive Cancer Network (2023)

The NCCN Guidelines for Lung Cancer Screening have evolved over time to reflect the latest evidence and expert consensus. These NCCN Guidelines have played a significant role in shaping clinical practice and policy, leading to increased payer coverage for lung cancer screening and decreasing lung cancer mortality. Continued research and advancements in early detection methods, along with the implementation of effective screening programs, will be crucial in the ongoing effort to reduce lung cancer mortality and improve the overall quality of life for patients affected by this disease.
Health System Recruitment and Retention Strategies: A Plenary Session
Authors: Rebecca L. Caires, Anne H. Gross, Todd A. Pickard, Kristi Stiffler, Timothy Kubal
Journal: Journal of the National Comprehensive Cancer Network (2023)

Recruitment and retention in healthcare were uniquely impacted by the COVID-19 pandemic. An existing workforce shortage was significantly exacerbated by high attrition, early retirements, and people leaving healthcare altogether because of burnout and exhaustion. Since the pandemic crisis has eased, individuals have shown the desire for healthier work–life balance and opportunities for remote or hybrid work environments with clearly defined career paths. Recognizing this shift and aligning with the current environment are imperative to recruiting and retaining employees in healthcare. At the NCCN 2023 Annual Conference, a panel of experts from 5 major academic oncology centers shared their struggles with recruitment and retention (both before and after the COVID-19 pandemic) and offered valuable insight into some of the systems and processes they’ve since implemented to attract desirable candidates, make them feel heard and appreciated, and retain them in the long run.
Updates in the Systemic Therapy Options for Clear Cell and Non–Clear Cell Renal Cell Carcinoma
Authors: Philippe E. Spiess, Peter A.S. Johnstone, Eric Jonasch
Journal: Journal of the National Comprehensive Cancer Network (2023)

At the NCCN 2023 Annual Conference, experts reviewed clinical data on established therapies for patients with metastatic renal cell carcinoma and discussed strategies to effectively manage both clear cell and non–clear cell tumor histologies in the setting of advanced stages. Depicted through 3 separate case studies, they strategized the selection of optimal first-line and subsequent-line therapies based on the individual case study and the tumor characteristics in each.
Management of Metastatic Prostate Cancer
Authors: Archana Ajmera, Rana R. McKay, Kelly L. Stratton
Journal: Journal of the National Comprehensive Cancer Network (2023)

Androgen deprivation therapy is a well-established standard of care for the management of metastatic prostate cancer; however, recent studies have investigated additional therapeutic options, escalation strategies, and primary directed therapy for patients with advanced disease. Treatment decisions are based on clinical parameters, disease characteristics, and patient factors. At the NCCN 2023 Annual Conference, a panel of experts used 3 case studies to develop an evidence-based approach for the treatment of patients with metastatic prostate cancer. The session focused on the current research regarding both systemic and local therapy options in each clinical context.
Best Practices for Addressing the Health Needs of the LGBTQ+ Community in Oncology Care
Authors: Bláz Bush, Paula Chambers Raney, Shail Maingi, Mandi L. Pratt-Chapman, None Scout, Clifford Goodman
Journal: Journal of the National Comprehensive Cancer Network (2023)

Patients with cancer in the LGBTQ+ community experience worse health outcomes when compared with their non-LGBTQ+ peers because of a variety of factors, including stigma, underrepresentation in research, lack of support, and implicit bias on the part of clinicians. For generations, many LGBTQ+ people have feared disclosing their identity to providers, leading to gaps in care and even higher mortality. As more people are identifying as members of the LGBTQ+ community, it’s crucial for providers to recognize them appropriately in healthcare, take steps such as acknowledging chosen names and pronouns, and provide care free from judgment. In today’s political climate, members of this community are facing increasing scrutiny, challenges, and barriers to accessing safe and affirming care. Providers can do their part to improve health outcomes among LGBTQ+ people by making their practices known as safe and affirming spaces, working to increase inclusivity in oncology care and improving data collection.
Management of Advanced Ovarian, Fallopian Tube, and Primary Peritoneal Cancers
Authors: Joyce F. Liu
Journal: Journal of the National Comprehensive Cancer Network (2023)

Treatment approaches for advanced ovarian cancer should consider several factors. Among the most important are platinum sensitivity, the status of BRCA and homologous recombination deficiency (HRD), and the changing indications for PARP inhibitors in recurrent disease and maintenance. PARP inhibitors have demonstrated clear benefit in patients with BRCA mutated tumors, especially in the first-line setting, and HRD testing can guide their use for patients without BRCA mutations. A new antibody–drug conjugate, mirvetuximab soravtansine, has been approved for use in a subset of patients with platinum-resistant disease. Newly diagnosed patients with advanced-stage ovarian, fallopian tube, or primary peritoneal cancers should always be evaluated by a gynecologic oncologist if possible.
New First-Line Systemic Treatment Options for Metastatic Esophageal Squamous Cell Carcinoma
Authors: Michael K. Gibson
Journal: Journal of the National Comprehensive Cancer Network (2023)

Esophageal squamous cell carcinoma is an aggressive malignancy with histologic variability depending on where in the world it is diagnosed, with most of these cancers occurring in China and other parts of Asia. Previous studies with cytotoxic chemotherapy combinations led to a plateau median overall survival of approximately 10 to 12 months, as well as a need for more effective treatment options. Cytotoxic chemotherapy served as the control arm in 3 studies that evaluated the safety and efficacy of immunotherapy + chemotherapy versus chemotherapy alone; in all 3 prospective randomized trials, the addition of immunotherapy resulted in a survival benefit in the first-line relapsed/metastatic setting. Data support these immunotherapy regimens as new standard-of-care systemic therapy options for unresectable, locally advanced, recurrent or metastatic esophageal cancers, and these regimens have now been incorporated into the NCCN Guidelines.
Sleep Disorders, Fatigue, and Cognitive Function in Cancer Survivors: A Plenary Session
Authors: Kristin Dickinson, Halle C.F. Moore, Jennifer Schmitz, Eric S. Zhou, Andrew T. Day
Journal: Journal of the National Comprehensive Cancer Network (2023)

For many patients, sleep disorders (particularly insomnia), cancer-related fatigue, and cancer-related cognitive impairment are common and distressing symptoms of cancer and its treatment. At the NCCN 2023 Annual Conference, a panel of experts began with a personal account of a cancer survivor’s experience and discussed approaches to assess and manage these adverse effects of cancer and its treatment.
Updates on the Management of Immunotherapy-Related Toxicities
Authors: Marianne Davies, Jordan McPherson, John A. Thompson
Journal: Journal of the National Comprehensive Cancer Network (2023)

With the increased use of immune checkpoint inhibition (ICI) comes an increase in the number of patients being treated for immune-related adverse events (irAEs). At the NCCN 2023 Annual Conference, presenters discussed 3 different types of irAEs, namely immune-mediated pneumonitis, major adverse cardiac events including myocarditis and myositis/myasthenia gravis overlap syndrome, and oral toxicities including mucositis and sicca syndrome. They emphasized the importance of considering comorbidities and infectious causes when treating immune pneumonitis. In the context of cardiac events during ICI therapy, the presentation highlighted the need for early detection and vigilance in recognizing insidious, nonspecific symptoms, particularly in cases involving myocarditis with myositis/myasthenia gravis overlap syndrome. Finally, the increasing recognition of oral toxicities was discussed, in addition to the importance of timely intervention to prevent long-term morbidity.
Management of Recurrent or Metastatic Cervical Cancer
Authors: Nadeem R. Abu-Rustum
Journal: Journal of the National Comprehensive Cancer Network (2023)

Cervical cancer often affects individuals aged &lt;50 years, with the main cause being a long-lasting infection with certain types of human papillomavirus (HPV). Prevention of cervical cancer includes screening tests and the HPV vaccine and, if found early, it can be treatable. Metastatic disease, however, is more lethal and is a significant problem worldwide due to screening and treatment limitations. Clinicians should discuss early detection options and treatment modalities with patients with cervical cancer for informed decision-making.
Management of Relapsed/Refractory Multiple Myeloma
Authors: Natalie S. Callander
Journal: Journal of the National Comprehensive Cancer Network (2023)

The treatment of relapsed multiple myeloma is based in part on the degree of previous exposure and resistance to commonly used drug classes. For patients with a first relapse, an anti-CD38 antibody–based combination is preferred unless patients have already received these agents, in which case a carfilzomib-based option can be an excellent choice. For patients with more refractory disease, a bispecific antibody is an emerging choice, but CAR T-cell therapy should also be considered for some patients; other options include salvage autologous transplantation, recycling of previous therapies, and selinexor-based therapies. Emerging new classes of drugs in development are poised to broaden the treatment possibilities for relapsed disease.